Mechanistic exploration of 6-shogaol’s preventive effects on azoxymethane and dextran sulfate sodium -induced colorectal cancer: involvement of cell proliferation, apoptosis, carcinoembryonic antigen, wingless-related integration site signaling, and oxido-inflammation

Abstract

Colorectal cancer (CRC) poses a significant global health burden, being the third most prevalent cancer and the second most significant contributor to cancer-related deaths worldwide. Preventive strategies are crucial to combat this rising incidence. 6-shogaol, derived from ginger, has shown promise in preventing and treating various cancers. This study investigated the preventive effects of 6-shogaol on azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC in mice. Forty male BALB/c mice were randomly divided into control, 6-shogaol, AOM + DSS, and 6-shogaol + AOM + DSS. Mice in the control group received corn oil for 16 weeks, while those in the 6-Shogaol group were administered 20 mg/kg of 6-shogaol for 16 weeks. The AOM + DSS group received a single intraperitoneal dose (<i>ip</i>) of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The 6-shogaol + AOM + DSS group received both 6-shogaol for 16 weeks and a single <i>ip</i> of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The AOM + DSS-treated mice exhibited reduced food consumption, colon weight, and colon length, along with increased tumor formation. Co-administration of 6-shogaol effectively reversed these changes, inhibiting CRC development. Histopathological analysis revealed protective effects of 6-shogaol against colonic insults and modulation of inflammatory responses. 6-shogaol significantly reduced Carcinoembryonic antigen and Kiel 67 levels, indicating inhibition of tumor cell proliferation. Mechanistically, 6-shogaol promoted apoptosis by upregulating protein 53 and caspase-3 expression, and it effectively restored the balance of the Wingless-related integration site signaling pathway by regulating β-catenin and adenomatous polyposis coli levels. Moreover, 6-shogaol demonstrated anti-inflammatory effects, reducing myeloperoxidase, Tumor necrosis factor alpha, and cyclooxygenase-2 levels in AOM/DSS-treated mice. Additionally, 6-shogaol restored redox homeostasis by reducing lipid peroxidation and nitrosative stress and enhancing antioxidant enzyme activities. The findings suggest that 6-shogaol inhibits cell proliferation, induces apoptosis, regulates Wnt signaling, suppresses inflammation, and restores redox homeostasis, providing comprehensive insights into its potential therapeutic benefits for CRC.